Inflammation context in Alzheimer's disease, a relationship intricate to define.

Alzheimer's disease (AD), the most common form of dementia, is characterized by the accumulation of amyloid ß (Aß) and hyperphosphorylated tau protein aggregates. Importantly, Aß and tau species are able to activate astrocytes and microglia, which release several proinflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß), together with reactive oxygen (ROS) and nitrogen species (RNS), triggering neuroinflammation. However, this inflammatory response has a dual function: it can play a protective role by increasing Aß degradation and clearance, but it can also contribute to Aß and tau overproduction and induce neurodegeneration and synaptic loss. Due to the significant role of inflammation in the pathogenesis of AD, several inflammatory mediators have been proposed as AD markers, such as TNF-α, IL-1ß, Iba-1, GFAP, NF-κB, TLR2, and MHCII. Importantly, the use of anti-inflammatory drugs such as NSAIDs has emerged as a potential treatment against AD. Moreover, diseases related to systemic or local inflammation, including infections, cerebrovascular accidents, and obesity, have been proposed as risk factors for the development of AD. In the following review, we focus on key inflammatory processes associated with AD pathogenesis.

[Immune checkpoint inhibitors. A breakthrough in cancer therapy]. / La inhibición de los puntos de control inmunológico, una terapia en evolución: remembranza del Premio Nobel de Medicina 2018.

Professors James P. Allison and Tasuku Honjo were awarded with the 2018 Nobel Prize in Medicine for their contributions in cancer immunotherapy. The latter is a breakthrough in cancer therapy, aimed to overcome tumor-induced immunosuppression, leading to the reactivation of the immune system against cancer cells. Under physiological conditions, the CTLA-4 and PD-1 proteins expressed on T-cells and discovered by the awarded scientists, lead to immune tolerance. Cancer cells exploit these control points to enhance the inhibition of T-cells. The expression of PD ligands (PD-L1) in tumor cells and CTLA-4 ligands in antigen presenting cells, which bind the PD-1 receptor and CTLA-4 respectively, block anti-tumor immunity. This situation led to a biotechnological race focused on the development of effective antibodies able to "turn-on" the immune system cheated by the tumor. Anti-CTLA-4 and anti-PD-1 antibodies improve life-expectancy in cancer patients. In this review, we perform an historical overview of Professors Allison and Honjo contribution, as well as the immunological basis of this new and powerful therapeutic strategy, highlighting the clinical benefits of such intervention.

La inhibición de los puntos de control inmunológico, una terapia en evolución: remembranza del Premio Nobel de Medicina 2018 / Immune checkpoint inhibitors: a breakthrough in cancer therapy

Professors James P. Allison and Tasuku Honjo were awarded with the 2018 Nobel Prize in Medicine for their contributions in cancer immunotherapy. The latter is a breakthrough in cancer therapy, aimed to overcome tumor-induced immunosuppression, leading to the reactivation of the immune system against cancer cells. Under physiological conditions, the CTLA-4 and PD-1 proteins expressed on T-cells and discovered by the awarded scientists, lead to immune tolerance. Cancer cells exploit these control points to enhance the inhibition of T-cells. The expression of PD ligands (PD-L1) in tumor cells and CTLA-4 ligands in antigen presenting cells, which bind the PD-1 receptor and CTLA-4 respectively, block anti-tumor immunity. This situation led to a biotechnological race focused on the development of effective antibodies able to "turn-on" the immune system cheated by the tumor. Anti-CTLA-4 and anti-PD-1 antibodies improve life-expectancy in cancer patients. In this review, we perform an historical overview of Professors Allison and Honjo contribution, as well as the immunological basis of this new and powerful therapeutic strategy, highlighting the clinical benefits of such intervention.

WNT Signaling Is a Key Player in Alzheimer's Disease.

The cellular processes regulated by WNT signaling have been mainly studied during embryonic development and cancer. In the last two decades, the role of WNT in the adult central nervous system has been the focus of interest in our laboratory. In this chapter, we will be summarized ß-catenin-dependent and -independent WNT pathways, then we will be revised WNT signaling function at the pre- and post-synaptic level. Concerning Alzheimer's disease (AD) initially, we found that WNT/ß-catenin signaling activation exerts a neuroprotective mechanism against the amyloid ß (Αß) peptide toxicity. Later, we found that WNT/ß-catenin participates in Tau phosphorylation and in learning and memory. In the last years, we demonstrated that WNT/ß-catenin signaling is instrumental in the amyloid precursor protein (APP) processing and that WNT/ß-catenin dysfunction results in Aß production and aggregation. We highlight the importance of WNT/ß-catenin signaling dysfunction in the onset of AD and propose that the loss of WNT/ß-catenin signaling is a triggering factor of AD. The WNT pathway is therefore positioned as a therapeutic target for AD and could be a valid concept for improving AD therapy. We think that metabolism and inflammation will be relevant when defining future research in the context of WNT signaling and the neurodegeneration associated with AD.

Bases biológicas del cáncer: una propuesta de contenidos mínimos para las carreras de la salud / Biological bases of cancer: a proposal of minimum contents for health schools

El cáncer constituye la segunda de causa de muerte a nivel mundial y se estima será la primera, superando a las cardiovasculares. El estudio de sus bases moleculares ha permitido el desarrollo de la quimioterapia clásica, como de nuevas terapias biológicas. Si bien estos avances han redundado en un aumento en la sobrevida, no ha impactado en una menor incidencia de los casos. Esto último se debe, en parte, al desconocimiento de los múltiples factores carcinogénicos existentes y los efectos de sus interacciones para cada uno de los tumores. En este sentido, es interesante notar que, en los currículos de las escuelas de salud de las universidades chilenas, el cáncer u oncología como tal, no constituye una cátedra en sí misma, siendo sus contenidos tangencialmente abordados en distintos momentos de la formación; en biología celular, medicina interna y cirugía, entre otros. Con estos antecedentes, el propósito de este trabajo es ofrecer un propuesta sencilla y accesible para los estudiantes, respecto de los contenidos que, a nuestro juicio, son esenciales para comprender las bases biológicas de esta enfermedad y enfrentar con mejores conocimientos el ciclo clínico posterior. A continuación, el lector se encontrará con principios fundamentales de la biología humana normal (como el ciclo celular y el dogma central de la biología molecular), que permiten obtener una visión global de los mecanismos fisiológicos cuya desregulación conlleva a una neoplasia maligna. Luego se entregarán algunas definiciones amplias en relación con los conceptos de neoplasia, tumor benigno y maligno. Para, finalmente, abordar las principales etapas que permiten el desarrollo del cáncer; (i) iniciación, (ii) promoción y (iii) progresión. En esta última, se profundizará por separado, en angiogénesis, degradación de la matriz extracelular, migración y evasión de la respuesta inmune. Este trabajo no aborda materias relacionadas con la hipótesis metabólica del cáncer.

Cancer constitutes the second most common cause of death worldwide and is expected to become the leading one, even above cardiovascular diseases. The understanding of the cellular and molecular basis of cancer has led not only to the proper development of chemotherapy but also of target therapies. Although these advances are related with improved survival rates among cancer patients, it has poorly impacted its incidences. In this regard, the lack of knowledge regarding the impact that the several carcinogenic factors and their interactions have on different types of cancers may explain at least in part the difficulties to reduce incidence rates. However, is worth noticing that in several health schools of chilean universities, cancer does not constitute a formal course, being only partially approached during other courses, such as cell biology, internal medicine, and surgery. Thus, the aim of our work is to provide students a simple and resumed manuscript about essential topics necessary to understand the biological basis of cancer. First, the reader will find some fundamentals about human biology including the cell cycle and the central dogma of molecular biology, which offers an overview of the physiological mechanisms leading to malignant neoplasia. Then, we will provide current definitions of neoplasia, benign and malignant tumors are provided. Finally, the different stages of tumor progression will be approached to allow the understanding of cancer development. These stages include (i) initiation, (ii) promotion, and (iii) progression. For the last one, metastasis, angiogenesis, extracellular matrix degradation, migration, and immune evasion will also be addressed. This work will not consider the metabolic hypothesis of cancer.

Andrographolide Reduces Neuroinflammation and Oxidative Stress in Aged Octodon degus.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder in which superior brain functions, such as memory and cognition, are impaired. Currently, no effective treatment is available for AD. Although andrographolide (ANDRO), a compound extracted from the herb Andrographis paniculata, has shown interesting effects in models of several diseases, including AD, its effects on other molecular changes observed in AD, such as neuroinflammation and oxidative stress, have not yet been studied. To evaluate the impact of ANDRO-based intervention on the levels of amyloid-ß (Aß) and neuroinflammatory and oxidative stress markers in the brains of aged Octodon degus, a Chilean rodent, fifty-six-month-old O. degus were treated intraperitoneally with 2 or 4 mg/kg ANDRO. Vehicle-injected and 12-month-old O. degus were used as positive controls. Then, the protein levels of selected markers were assessed via immunohistochemistry and immunoblotting. ANDRO significantly reduced the total Aß burden as well as astrogliosis and interleukin-6 levels. Moreover, ANDRO significantly reduced the levels of 4-hydroxynonenal and N-tyrosine adducts, suggesting a relevant reduction in oxidative stress within aged O. degus brain. Considering that O. degus has been proposed as a potential "natural" model for sporadic AD due to the development of neuropathological markers that resemble this pathology, our results suggest that ANDRO should be further studied to establish its potential as a therapeutic drug for AD.

Wnt Signaling Upregulates Teneurin-3 Expression via Canonical and Non-canonical Wnt Pathway Crosstalk.

Teneurins (Tens) are a highly conserved family of proteins necessary for cell-cell adhesion. Tens can be cleaved, and some of their proteolytic products, such as the teneurin c-terminal associated-peptide (TCAP) and the intracellular domain (ICD), have been demonstrated to be biologically active. Although Tens are considered critical for central nervous system development, they have also been demonstrated to play important roles in adult tissues, suggesting a potential link between their deregulation and various pathological processes, including neurodegeneration and cancer. However, knowledge regarding how Ten expression is modulated is almost absent. Relevantly, the functions of Tens resemble several of the effects of canonical and non-canonical Wnt pathway activation, including the effects of the Wnt pathways on neuronal development and function as well as their pivotal roles during carcinogenesis. Accordingly, in this initial study, we decided to evaluate whether Wnt signaling can modulate the expression of Tens. Remarkably, in the present work, we used a specific inhibitor of porcupine, the key enzyme for Wnt ligand secretion, to not only demonstrate the involvement of Wnt signaling in regulating Ten-3 expression for the first time but also reveal that Wnt3a, a canonical Wnt ligand, increases the expression of Ten-3 through a mechanism dependent on the secretion and activity of the non-canonical ligand Wnt5a. Although our work raises several new questions, our findings seem to demonstrate the upregulation of Ten-3 by Wnt signaling and also suggest that Ten-3 modulation is possible because of crosstalk between the canonical and non-canonical Wnt pathways.

Revisiting the Paraquat-Induced Sporadic Parkinson's Disease-Like Model.

Parkinson's disease (PD) is a major neurodegenerative disorder that affects 1-2% of the total global population. Despite its high prevalence and publication of several studies focused on understanding its pathology, an effective treatment that stops and/or reverses the damage to dopaminergic neurons is unavailable. Similar to other neurodegenerative disorders, PD etiology may be linked to several factors, including genetic susceptibility and environmental elements. Regarding environmental factors, several neurotoxic pollutants, including 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), have been identified. Moreover, some pesticides/herbicides, such as rotenone, paraquat (PQ), maneb (MB), and mancozeb (MZ), cause neurotoxicity and induce a PD-like pathology. Based on these findings, several in vitro and in vivo PD-like models have been developed to understand the pathophysiology of PD and evaluate different therapeutic strategies to fight dopaminergic neurodegeneration. 6-OHDA and MPTP are common models used in PD research, and pesticide-based approaches have become secondary models of study. However, some herbicides, such as PQ, are commonly used by farming laborers in developing countries. Thus, the present review summarizes the relevant scientific background regarding the use and effects of chronic exposure to PQ in the context of PD. Similarly, we discuss the relevance of PD-like models developed using this agrochemical compound.

Wnt-induced activation of glucose metabolism mediates the in vivo neuroprotective roles of Wnt signaling in Alzheimer disease.

Dysregulated Wnt signaling is linked to major neurodegenerative diseases, including Alzheimer disease (AD). In mouse models of AD, activation of the canonical Wnt signaling pathway improves learning/memory, but the mechanism for this remains unclear. The decline in brain function in AD patients correlates with reduced glucose utilization by neurons. Here, we test whether improvements in glucose metabolism mediate the neuroprotective effects of Wnt in AD mouse model. APPswe/PS1dE9 transgenic mice were used to model AD, Andrographolide or Lithium was used to activate Wnt signaling, and cytochalasin B was used to block glucose uptake. Cognitive function was assessed by novel object recognition and memory flexibility tests. Glucose uptake and the glycolytic rate were determined using radiotracer glucose. The activities of key enzymes of glycolysis such as hexokinase and phosphofructokinase, Adenosine triphosphate (ATP)/Adenosine diphosphate (ADP) levels and the pentose phosphate pathway and activity of glucose-6 phosphate dehydrogenase were measured. Wnt activators significantly improved brain glucose utilization and cognitive performance in transgenic mice. Wnt signaling enhanced glucose metabolism by increasing the expression and/or activity of hexokinase, phosphofructokinase and AMP-activated protein kinase. Inhibiting glucose uptake partially abolished the beneficial effects of Wnt signaling on learning/memory. Wnt activation also enhanced glucose metabolism in cortical and hippocampal neurons, as well as brain slices derived from APPswe/PS1E9 transgenic mice. Combined, these data provide evidence that the neuroprotective effects of Wnt signaling in AD mouse models result, at least in part, from Wnt-mediated improvements in neuronal glucose metabolism.

New Insights into the Spontaneous Human Alzheimer's Disease-Like Model Octodon degus: Unraveling Amyloid-ß Peptide Aggregation and Age-Related Amyloid Pathology.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Despite advances in our understanding of the molecular milieu driving AD pathophysiology, no effective therapy is currently available. Moreover, various clinical trials have continued to fail, suggesting that our approach to AD must be revised. Accordingly, the development and validation of new models are highly desirable. Over the last decade, we have been working with Octodon degus (degu), a Chilean rodent, which spontaneously develops AD-like neuropathology, including increased amyloid-ß (Aß) aggregates, tau hyperphosphorylation, and postsynaptic dysfunction. However, for proper validation of degu as an AD model, the aggregation properties of its Aß peptide must be analyzed. Thus, in this study, we examined the capacity of the degu Aß peptide to aggregate in vitro. Then, we analyzed the age-dependent variation in soluble Aß levels in the hippocampus and cortex of third- to fifth-generation captive-born degu. We also assessed the appearance and spatial distribution of amyloid plaques in O. degus and compared them with the plaques in two AD transgenic mouse models. In agreement with our previous studies, degu Aß was able to aggregate, forming fibrillar species in vitro. Furthermore, amyloid plaques appeared in the anterior brain structures of O. degus at approximately 32 months of age and in the whole brain at 56 months, along with concomitant increases in Aß levels and the Aß42/Aß40 ratio, indicating that O. degus spontaneously develops AD-like pathology earlier than other spontaneous models. Based on these results, we can confirm that O. degus constitutes a valuable model to improve AD research.

Neuroprotective Effects of Ferruginol, Jatrophone, and Junicedric Acid Against Amyloid-ß Injury in Hippocampal Neurons.

Soluble amyloid-ß (Aß) oligomers have been recognized as early neurotoxic intermediates with a key role in the synaptic dysfunction observed in Alzheimer's disease (AD). Aß oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Additionally, the presence of Aß oligomers is associated with imbalanced intracellular calcium levels and apoptosis in neurons. In this context, we evaluated the effects of three diterpenes (ferruginol, jatrophone, and junicedric acid) that are found in medicinal plants and have several forms of biological activity. The intracellular calcium levels in hippocampal neurons increased in the presence of ferruginol, jatrophone, and junicedric acid, a result that was consistent with the observed increase in CA1 synaptic transmission in mouse hippocampal slices. Additionally, assays using Aß peptide demonstrated that diterpenes, particularly ferruginol, restore LTP and reduce apoptosis. Recovery of the Aß oligomer-induced loss of the synaptic proteins PSD-95, synapsin, VGlut, and NMDA receptor subunit 2A was observed in mouse hippocampal slices treated with junicedric acid. This cascade of events may be associated with the regulation of kinases, e.g., protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII), in addition to the activation of the canonical Wnt signaling pathway and could thus provide protection against Aß oligomers, which trigger synaptic dysfunction. Our results suggest a potential neuroprotective role for diterpenes against the Aß oligomers-induced neurodegenerative alterations, which make them interesting molecules to be further studied in the context of AD.

INT131 increases dendritic arborization and protects against Aß toxicity by inducing mitochondrial changes in hippocampal neurons.

In previous studies, we have demonstrated the beneficial effects of classic PPARγ agonists on neuroprotection against Aß oligomer neurotoxicity in a double transgenic mouse model of Alzheimer' disease (AD). INT-131, a novel, non-thiazolidinedione compound that belongs to a new family of drugs, selective PPARγ modulators (SPPARMs), has provided an emerging opportunity for the treatment of type 2 diabetes mellitus and metabolic syndrome. However, its role in the central nervous system has not been studied. The aim of this study was to evaluate the putative neuroprotective role of INT131 in hippocampal neurons. We found that INT131 increased dendritic branching, promoted neuronal survival against Aß amyloid, increased expression of PGC1-1α and modulated neuronal mitochondrial dynamics. Our results suggest that INT131, a drug that has been shown to be safe and effective in metabolic disorders, may constitute a new therapeutic alternative for AD.

Wnt/TLR Dialog in Neuroinflammation, Relevance in Alzheimer's Disease.

The innate immune system (IIS) represents the first line of defense against exogenous and endogenous harmful stimuli. Different types of pathogens and diverse molecules can activate the IIS via a ligand-receptor mechanism. Cytokine release, recruitment of immunocompetent cells, and inflammation constitute the initial steps in an IIS-mediated response. While balanced IIS activity can resolve a harmful event, an altered response, such as deficient or persistent IIS activity, will have a critical effect on organism homeostasis. In this regard, chronic IIS activation has been associated with a wide range of diseases, including chronic inflammatory disorders (inflammatory bowel disease, arthritis, chronic obstructive pulmonary disease, among others), cancer and, more recently, neurodegenerative disorders. The relevance of the immune response, particularly inflammation, in the context of neurodegeneration has motivated rigorous research focused on unveiling the mechanisms underlying this response. Knowledge regarding the molecular hallmarks of the innate immune response and understanding signaling pathway cross talk are critical for developing new therapeutic strategies aimed at modulating the neuroinflammatory response within the brain. In the present review, we discuss the IIS in the central nervous system, particularly the cross talk between the toll-like receptor-signaling cascade and the wingless-related MMTV integration site (Wnt) signaling pathway and its relevance in neurodegenerative disorders such as Alzheimer's disease.

PPARs in the central nervous system: roles in neurodegeneration and neuroinflammation.

Over 25 years have passed since peroxisome proliferators-activated receptors (PPARs), were first described. Like other members of the nuclear receptors superfamily, PPARs have been defined as critical sensors and master regulators of cellular metabolism. Recognized as ligand-activated transcription factors, they are involved in lipid, glucose and amino acid metabolism, taking part in different cellular processes, including cellular differentiation and apoptosis, inflammatory modulation and attenuation of acute and chronic neurological damage in vivo and in vitro. Interestingly, PPAR activation can simultaneously reprogram the immune response, stimulate metabolic and mitochondrial functions, promote axonal growth, induce progenitor cells to differentiate into myelinating oligodendrocytes, and improve brain clearance of toxic molecules such as ß-amyloid peptide. Although the molecular mechanisms and cross-talk with different molecular pathways are still the focus of intense research, PPARs are considered potential therapeutic targets for several neuropathological conditions, including degenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease. This review considers recent advances regarding PPARs, as well as new PPAR agonists. We focus on the mechanisms behind the neuroprotective effects exerted by PPARs and summarise the roles of PPARs in different pathologies of the central nervous system, especially those associated with degenerative and inflammatory mechanisms.

Recent Advances in Neuroinflammation Therapeutics: PPARs/LXR as Neuroinflammatory Modulators.

Neurodegenerative disorders are one of the most critical public health concerns of our times. Regrettably, therapeutic interventions currently available have shown only partial benefits to patients affected by one of these disorders. Although the important advances made during the last decades, several questions regarding physiopathological aspects of these diseases are still open. On this regard, the role of neuroinflammation is recognized as critical during the establishment and progression of the neurodegenerative process, and several authors have suggested that neuroinflammatory modulation should be at the basis of therapeutic treatment. In the present review we summarize the general aspects of the neuroinflammatory process and the cellular component of such response whose have been commonly related with the main neurodegenerative disorders, particularly Alzheimer's and Parkinson's disease, as well as, the main molecular events that might trigger the inflammatory process and affect neuronal support structures, such as the blood brain barrier, leading to neurodegeneration. Additionally, we discuss recent advances regarding Nuclear Receptors research, such as peroxisome proliferators-activated receptors and liver X receptor, and the molecular basis of its potential role against neuroinflammation and neurodegeneration.

Teneurins and Alzheimer's disease: a suggestive role for a unique family of proteins.

Alzheimer's disease is a debilitating age-related disorder characterized by distinct pathological hallmarks, such as progressive memory loss and cognitive impairment. During the last few years, several cellular signaling pathways have been associated with the pathogenesis of Alzheimer's disease, such as Notch, mTOR and Wnt. However, the potential factors that modulate these pathways and novel molecular mechanisms that might account for the pathogenesis of Alzheimer's disease or for therapy against this disease are still matters of intense research. Teneurins are members of a unique protein system that has recently been proposed as a novel and highly conserved regulatory signaling system in the vertebrate brain, so far related with neurite outgrowth and neuronal matching. The similitude in structure and function of teneurins with other cellular signaling pathways, suggests that they may play a critical role in Alzheimer's disease, either through the modulation of transcription factors due to the nuclear translocation of the teneurins intracellular domain, or through the activity of the corticotrophin releasing factor (CRF)-like peptide sequence, called teneurin C-terminal associated peptide. Moreover, the presence of Ca(2+)-binding motifs within teneurins structure and the Zic2-mediated Wnt/ß-catenin signaling modulation, allows hypothesize a potential crosslink between teneurins and the Wnt signaling pathway, particularly. Herein, we aim to highlight the main characteristics of teneurins and propose, based on current knowledge of this family of proteins, an interesting review of their potential involvement in Alzheimer's disease.

Age Progression of Neuropathological Markers in the Brain of the Chilean Rodent Octodon degus, a Natural Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of age-related dementia worldwide. Several models for AD have been developed to provide information regarding the initial changes that lead to degeneration. Transgenic mouse models recapitulate many, but not all, of the features of AD, most likely because of the high complexity of the pathology. In this context, the validation of a wild-type animal model of AD that mimics the neuropathological and behavioral abnormalities is necessary. In previous studies, we have reported that the Chilean rodent Octodon degus could represent a natural model for AD. In the present work, we further describe the age-related neurodegeneration observed in the O. degus brain. We report some histopathological markers associated with the onset progression of AD, such as glial activation, increase in oxidative stress markers, neuronal apoptosis and the expression of the peroxisome proliferative-activated receptor γ coactivator-1α (PGC-1α). With these results, we suggest that the O. degus could represent a new model for AD research and a powerful tool in the search for therapeutic strategies against AD.

Alzheimer's disease: relevant molecular and physiopathological events affecting amyloid-ß brain balance and the putative role of PPARs.

Alzheimer's disease (AD) is the most common form of age-related dementia. With the expected aging of the human population, the estimated morbidity of AD suggests a critical upcoming health problem. Several lines of research are focused on understanding AD pathophysiology, and although the etiology of the disease remains a matter of intense debate, increased brain levels of amyloid-ß (Aß) appear to be a critical event in triggering a wide range of molecular alterations leading to AD. It has become evident in recent years that an altered balance between production and clearance is responsible for the accumulation of brain Aß. Moreover, Aß clearance is a complex event that involves more than neurons and microglia. The status of the blood-brain barrier (BBB) and choroid plexus, along with hepatic functionality, should be considered when Aß balance is addressed. Furthermore, it has been proposed that exposure to sub-toxic concentrations of metals, such as copper, could both directly affect these secondary structures and act as a seeding or nucleation core that facilitates Aß aggregation. Recently, we have addressed peroxisomal proliferator-activated receptors (PPARs)-related mechanisms, including the direct modulation of mitochondrial dynamics through the PPARγ-coactivator-1α (PGC-1α) axis and the crosstalk with critical aging- and neurodegenerative-related cellular pathways. In the present review, we revise the current knowledge regarding the molecular aspects of Aß production and clearance and provide a physiological context that gives a more complete view of this issue. Additionally, we consider the different structures involved in AD-altered Aß brain balance, which could be directly or indirectly affected by a nuclear receptor (NR)/PPAR-related mechanism.

Signaling pathway cross talk in Alzheimer's disease.

Numerous studies suggest energy failure and accumulative intracellular waste play a causal role in the pathogenesis of several neurodegenerative disorders and Alzheimer's disease (AD) in particular. AD is characterized by extracellular amyloid deposits, intracellular neurofibrillary tangles, cholinergic deficits, synaptic loss, inflammation and extensive oxidative stress. These pathobiological changes are accompanied by significant behavioral, motor, and cognitive impairment leading to accelerated mortality. Currently, the potential role of several metabolic pathways associated with AD, including Wnt signaling, 5' adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1), and peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) have widened, with recent discoveries that they are able to modulate several pathological events in AD. These include reduction of amyloid-ß aggregation and inflammation, regulation of mitochondrial dynamics, and increased availability of neuronal energy. This review aims to highlight the involvement of these new set of signaling pathways, which we have collectively termed "anti-ageing pathways", for their potentiality in multi-target therapies against AD where cellular metabolic processes are severely impaired.